小乙型肝炎病毒表面抗原通過內質網應激誘導的FGF19 / JAK2 / ST

StephenW

Small hepatitis B virus surface antigen promotes malignant progression of hepatocellular carcinoma via endoplasmic reticulum stress-induced FGF19/JAK2/STAT3 signaling
Shuxiang Wu  1 , Shuangshuang Ye  1 , Xiaohan Lin  2 , Yan Chen  1 , Yi Zhang  1 , Zhentang Jing  1 , Wei Liu  1 , Wannan Chen  3 , Xinjian Lin  4 , Xu Lin  5
Affiliations
Affiliations

    1
    Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China.
    2
    Department of Gastrointestinal Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.
    3
    Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China; Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China.
    4
    Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China. Electronic address: [email protected].
    5
    Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China; Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China. Electronic address: [email protected].

    PMID: 33249195 DOI: 10.1016/j.canlet.2020.11.032

Abstract

Chronic hepatitis B virus (HBV) infection is one of the major global health problems. Although the small protein of hepatitis B virus surface antigen (HBsAg), SHBs, is the most abundant HBV viral protein, its pathogenic role and molecular mechanism in malignant progression of HBV-related hepatocellular carcinoma (HCC) remain largely unknown. Here we reported that SHBs expression induced epithelial-mesenchymal transition (EMT) process in HCC cells and significantly increased their migratory and invasive ability as well as metastatic potential. Mechanistically, SHBs expression in HCC cells induced endoplasmic reticulum (ER) stress that activated the activating transcription factor 4 (ATF4) to increase the expression and secretion of fibroblast growth factor 19 (FGF19). The autocrine released FGF19 in turn activated JAK2/STAT3 signaling for induction of EMT process in HCC. Notably, SHBs was positively correlated with the expression of mesenchymal markers, the phosphorylation status of JAK2 and STAT3 as well as FGF19 levels in human HCC samples. HCC patients with SHBs positive had a more advanced clinical stage and worse prognosis. These results suggest an important role of SHBs in the metastasis and progression of HCC and may highlight a potential target for preventive and therapeutic intervention of HBV-related HCC and its malignant progression.

Keywords: Fibroblast growth factor 19; HBV small Surface proteins; Hepatitis B virus; Invasion and metastasis; Liver cancer.

Copyright © 2020. Published by Elsevier B.V.

StephenW

小乙型肝炎病毒表面抗原通過內質網應激誘導的FGF19 / JAK2 / STAT3信號傳導促進肝癌的惡性進展
吳淑香1，雙雙葉1，林小涵2，陳艷1，張藝1，振堂經1，劉偉1，陳萬南3，林新健4，徐林5
隸屬關係
隸屬關係

    1個
    胃腸癌教育部重點實驗室（福建醫科大學），福州
    2
    福建醫科大學附屬第一醫院胃腸外科，福州。
    3
    胃腸道腫瘤教育部重點實驗室（福建醫科大學）福建醫科大學醫學微生物學系福建省腫瘤微生物學重點實驗室，福州。
    4
    胃腸道癌教育部重點實驗室（福建醫科大學），福州電子地址：[email protected]。
    5
    胃腸道腫瘤教育部重點實驗室（福建醫科大學）福建醫科大學醫學微生物學系福建省腫瘤微生物學重點實驗室，福州。電子地址：[email protected]。

    PMID：33249195 DOI：10.1016 / j.canlet.2020.11.032

抽象

慢性乙型肝炎病毒（HBV）感染是全球主要的健康問題之一。儘管乙型肝炎病毒表面抗原（HBsAg）的小蛋白是最豐富的HBV病毒蛋白，但其在HBV相關肝細胞癌（HCC）惡性進展中的致病作用和分子機制仍然未知。在這裡，我們報導了SHBs的表達在HCC細胞中誘導了上皮-間質轉化（EMT）過程，並顯著提高了它們的遷移和侵襲能力以及轉移潛力。從機制上講，HCC細胞中SHB的表達會誘導內質網（ER）應激，從而激活活化轉錄因子4（ATF4）以增加成纖維細胞生長因子19（FGF19）的表達和分泌。自分泌釋放的FGF19依次激活JAK2 / STAT3信號傳導，以誘導HCC中的EMT過程。值得注意的是，SHBs與人肝癌樣本中的間充質標誌物的表達，JAK2和STAT3的磷酸化狀態以及FGF19水平呈正相關。 SHBs陽性的HCC患者臨床階段更晚期，預後更差。這些結果表明，SHBs在HCC的轉移和進展中具有重要作用，並且可能突出顯示HBV相關HCC及其惡性進展的預防和治療干預的潛在目標。

關鍵詞：成纖維細胞生長因子19； HBV小表面蛋白；乙型肝炎病毒;侵襲和轉移；肝癌。

版權所有©2020。由Elsevier B.V.發布。

StephenW

https://www.sciencedirect.com/sc ... 20306303?via%3Dihub